Depression is a most common mental disorder with a morbidity of around 5% of the world's population harming the physical and mental health of human beings as well as seriously affecting people's quality of life. It is predicted that by 2020, depression will be the second major disease causing health problems and life span shortening of human beings.
The mechanism about how antidepressants function is not yet well elucidated. Medications with explicit effects on depression are substantially targeting the synapses on the nerve terminals and exert therapeutic roles by regulating the level of synaptic cleft neurotransmitters. Biochemical research on etiology of depression indicates that the depression is mainly related to the following 5 types of neurotransmitters among others: 5-hydroxy tryptamine (5-HT), noradrenaline (NA), dopamine (DA), acetylcholine (Ach) and γ-aminobutyric acid (GABA).
Antidepressants can be categorized into two families: the early non-selective antidepressants and the novel selective reuptake inhibitors. Non-selective antidepressants mainly include the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). Selective reuptake inhibitors are comprised of (1) selective serotonin (5-HT) reuptake inhibitors (SSRIs), such as Fluoxetine and Paroxetine; (2) noradrenaline reuptake inhibitors (NRIs) such as Reboxitine; (3) noradrenaline and dopamine reuptake inhibitors (NDRIs) such as Mirtazapine; (4) 5-HT and NA dual reuptake inhibitors (SNRIs) such as Venlafaxine and Duloxetine; (5) 5-HT reuptake enhancers such as Tianeptine et al.
Although a variety of antidepressants are used clinically, the development thereof is still a hotspot in the research on novel drugs due to several factors including that some of the medications have low response rate and potential adverse effect, and that there are still considerable patients who have not been treated effectively with all kinds of medications and some of whom may even require the use of electro-convulsive therapy. Vast amount of fundings from many pharmaceutical companies has been invested into the development of a more promising drug.
The global research trend in antidepressant development mainly lies in two aspects:
One is the secondary development of the existing drugs including 1) further exploiting their new indications and 2) changing the present dosage forms of the existing drugs.
The other is the development of new products. Novel antidepressants with better antidepressive effects, shorter onset time of drug and greater safty than the commercially available drugs can be developed by searching for compounds of new structural type which will act on a new target of multiple targets of this specific disease.
Research on the selective triple reuptake inhibitors, among others coducted on new antidepressants, is now getting more and more attention and is expected to solve the problem about delayed effects that the present antidepressants have, to improve efficacies and to enhance the safty of the drugs. Triple reuptake inhibitors also known as “broad spectrum” antidepressants are referred to a class of compound which simultaneously and selectively inhibit the reuptake of three monoamine neurotransmitters that are closely associated with the depression, namely 5-HT, NA and DA.
Studies on triple reuptake inhibitors are still in the clinical phase. For example, a triple reuptake inhibitor DOV-21947 developed by DOV Pharmaceutical. Inc. is in phase II clinical trial and NS-2359 co-developed by GSK and NeuroSearch is in phase II clinical trial as well. These triple reuptake inhibitors of monoamine neurotransmitter with the advantages of high efficiency, fast onset of action and so on, are becoming the primary focus in the andepressant field. In our country, research and development about novel antidepressive drugs is still in the preliminary stage. Research on novel antidepressants, especially on those targeting the triple pathway of the 5-HT, NA and DA system, becomes an important subject and is currently attracting numerous interests.